This invention relates to heteroarylpiperidines, pyrrolidines and piperazines. More particularly, this invention relates to heteroarylpiperidines, pyrrolidines and piperazines having antipsychotic activity and to their use as antipsychotic drugs.
The therapeutic treatment of schizophrenic patients by administration of neuroleptic drugs, such as chlorpromazine, haloperidol, sulpiride, and chemically closely related compounds, is widespread. While control of schizophrenic symptoms has been successful, treatment with these drugs does not cure the psychotic patient, who will almost certainly relapse if medication is discontinued. There exists a continuing need in the art for antipsychotic drugs for the treatment of psychoses.
Moreover, some of the known neuroleptics produce unwanted side effects. For example, the side effects of many antipsychotic drugs include the so-called extrapyramidal symptoms, such as rigidity and tremor, continuous restless walking, and tardive dyskinesia which causes facial grimacing, and involuntary movements of the face and extremities. Orthostatic hypotension is also common. Thus, there also exists a need in the art for antipsychotic drugs that produce fewer or less severe manifestations of these common side effects.
In addition, because of the frequent long term administration of neuroleptics and the problems with patient compliance, there is a further need in the art for long lasting neuroleptics, which can be formulated into sustained release depot preparations, without the side effects previously mentioned.
Moreover, there has been a need for drugs that can produce other biological effects. For example, relief from pain has been an age-old aspiration which has led to the discovery of natural and synthetic analgetics. Nevertheless, the need for safe and effective analgetics has continued to the present day.
This invention aids in fulfilling these needs in the art by providing a compound of the formula: 
wherein
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(R2)xe2x80x94
R2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl and phenylsulfonyl groups;
p is 1 or 2;
Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino;
Q1 is selected from the group consisting of: 
xe2x80x83where Z is 
xe2x80x83and
Y2 is selected from the group consisting of: 
in which (R1) is xe2x80x94CR24R27xe2x80x94(CR23R24)nxe2x80x94CR24R27xe2x80x94 where n is 0,1,2, or 3; or
xe2x80x94CHR24xe2x80x94CHxe2x95x90CHxe2x80x94CHR24xe2x80x94,
xe2x80x94CHR24xe2x80x94Cxe2x95x90Cxe2x80x94CHR24xe2x80x94,
xe2x80x94CHR24xe2x80x94CHxe2x95x90CHxe2x80x94CR23R24xe2x80x94CHR24xe2x80x94,
xe2x80x94CHR24xe2x80x94CR23R24xe2x80x94CHxe2x95x90CHxe2x80x94CHR24xe2x80x94,
xe2x80x94CHR24xe2x80x94Cxe2x89xa1Cxe2x80x94CR23R24xe2x80x94CHR24xe2x80x94, or
xe2x80x94CHR24xe2x80x94CR23R24xe2x80x94Cxe2x89xa1Cxe2x80x94CHR24xe2x80x94,
the xe2x80x94CHxe2x95x90CHxe2x80x94 bond being cis or trans;
R and m are as defined hereinafter;
R23 is hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, arylalkyloxy, alkanoyloxy, hydroxy lower alkyl, alkoxy lower alkyl, aryloxy lower alkyl, arylalkyl oxy lower alkyl, alkanoyloxy lower alkyl or 
where Z1 is lower alkyl, xe2x80x94OH, lower alkoxy, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94NH2 or halogen; and
R24 is hydrogen, alkyl, aryl, hydroxy lower alkyl, alkoxy lower alkyl, aryloxy lower alkyl, arylalkoxy lower alkyl, alkanoyloxy lower alkyl or 
where Z1 is as previously defined;
R27 is hydrogen or R24 and R27 taken together with the carbon to which they are attached form Cxe2x95x90O or Cxe2x95x90S;
and R and m are as defined hereinafter; 
where R1 is as previously defined, and R3 is hydrogen or xe2x80x94OCH3; 
where R1 is as previously defined; and
R4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C1-C6alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C1-C18)acyl amino, (C1-C18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, nitro, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94(C1-C18 straight or branched chain) alkyl or xe2x80x94C(xe2x95x90O)-aryl;
in which aryl is phenyl or 
where R5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; 
where R1 and R4 are as previously defined; 
where either one of Xy or Xz is xe2x80x94C(xe2x95x90O)xe2x80x94 and the other is xe2x80x94CH2xe2x80x94; and
R5xe2x80x2 is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine; and
R1 is as previously defined; 
where R1 and R4 are as previously defined; 
where A is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94C(xe2x95x90CH2)xe2x80x94, xe2x80x94C(xe2x95x90O)CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CR26xe2x95x90Nxe2x80x94, or xe2x80x94CR25R26xe2x80x94;
R25 is hydrogen, lower alkyl, hydroxy or alkanoyloxy;
R26 is hydrogen or lower alkyl;
either one of By and Bz is CH or N and the other is CH;
U is O or S;
q is 1, 2, 3 or 4, and R1 and R4 are as previously defined; 
where R1 is as previously defined; 
wherein R1, R4 and q are as defined above; and
R28 is hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl or substituted phenyl; 
wherein R1, R4 and q are as defined above;
R29 and R30 are hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl or substituted phenyl;
R31 and R32 are hydrogen, hydroxy, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl, substituted phenyl, hydroxymethyl, or CHOR33 where R33 is (C1-C18)alkanoyl; or
either R29 and R30 taken together or R31 and R32 taken together with the carbon group to which they are attached form a Cxe2x95x90O or Cxe2x95x90S group; 
where R1, R4, R28, R29, R30, R31, R32 and q are as defined above; 
where R1, R4, R28, R29, R30, R31, R32 and q are as defined above; 
wherein R1 and R4 are previously defined and m is defined hereinafter; 
where R1 is as previously defined;
Q is S, NH, or xe2x80x94CH2xe2x80x94; and
R and m are as defined hereinafter; 
where R1 is as previously defined; 
where R1, and R4 are as previously defined and m is as defined hereinafter; 
where R1, R4 are as previously defined and m is as defined hereinafter;
xe2x80x94R1xe2x80x94Oxe2x80x94R12xe2x80x83xe2x80x83(18)
where R12 is selected from the group consisting of:
hydrogen,
alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C18 straight chain or branched) alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94NR13R14,
xe2x80x94C(xe2x95x90O)xe2x80x94NR15R16,
xe2x80x94S(xe2x95x90O)2xe2x80x94R17, and 
where R13 is selected from the group consisting of hydrogen and (C1-C18)alkyl groups;
where R14 is selected from the group consisting of hydrogen and (C1-C18)alkyl groups;
where NR5R16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;
where R17 is selected from the group consisting of lower alkyl and aryl groups;
where R4 is previously defined and m is defined hereinafter;
xe2x80x94R1xe2x80x94NR18R19xe2x80x83xe2x80x83(19)
where R18 and R19 are independently selected from the group consisting of:
hydrogen,
(C1-C12 straight or branched chain) alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94(C1-C18) alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C18) alkyl;
xe2x80x94C(xe2x95x90O)-pyridyl or 
where NR18R19 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; where the piperidinyl or piperazinyl ring is optionally substituted by 
where R1, X, Y, p, R4 and R28 are as previously defined and m is defined hereinafter;
xe2x80x94R1xe2x80x94Sxe2x80x94R12xe2x80x83xe2x80x83(20)
where R1 and R12 are as previously defined; 
where R1, R4 and R28 are as previously defined; and
where
R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl,
xe2x80x94C(xe2x95x90O)-alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94O-alkyl,
xe2x80x94C(xe2x95x90O)-aryl,
xe2x80x94C(xe2x95x90O)-heteroaryl,
xe2x80x94CH(OR7)-alkyl,
xe2x80x94C(xe2x95x90W)-alkyl,
xe2x80x94C(xe2x95x90W)-aryl, and
xe2x80x94C(xe2x95x90W)-heteroaryl;
alkyl is (C1-C18)alkyl;
aryl is as previously defined; 
Q3 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94;
W is CH2 or CHR8 or Nxe2x80x94R9;
R7 is hydrogen, alkyl, or alkanoyl;
R8 is lower alkyl;
R9 is hydroxy, alkoxy, or xe2x80x94NHR10; and
R10 is hydrogen, alkyl, (C1-C3)acyl, aryl, xe2x80x94C(xe2x95x90O)aryl or xe2x80x94C(xe2x95x90O)heteroaryl, where aryl and heteroaryl are as defined above; and
m is 1, 2, or 3;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94Sxe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, Y is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy or trifluoromethyl, and p is 1 or 2;
with the proviso that in formula (4) R4 is not H when R1 is xe2x80x94(CH2)2-5xe2x80x94, Z is not 
xe2x80x83X is xe2x80x94Sxe2x80x94, Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl, and p is 1 or 2;
with the proviso, that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94NHxe2x80x94 or xe2x80x94N(R2)xe2x80x94, Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl and Q2 is xe2x80x94CH2xe2x80x94;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94Oxe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, Y is hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen, and p is 1 or 2;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94Sxe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2, R is hydrogen, and m is 1;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94N(R2)xe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, R is chlorine, fluorine, bromine, iodine, lower alkyl, lower alkoxy, lower alkyl thio, lower mono- or dialkylamino, amino, cyano, hydroxy, trifluoromethyl; R2 is aryl; Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94NHxe2x80x94 or xe2x80x94N(R2)xe2x80x94, where R2 is lower alkyl, aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2 and Q2 is xe2x80x94CH2xe2x80x94;
with the proviso that Y2 is not the moiety of formula (8) when Z is 
xe2x80x83X is O, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;
with the proviso that in formula (1) Z is not 
xe2x80x83when X is O or S, Y is hydrogen, R is hydrogen, (C1-C4)alkyl, chlorine, fluorine, bromine, iodine, cyano, (C1-C4)alkoxy, aryl, xe2x80x94COOR25 where R25 is (C1-C4)alkyl;
with the proviso that in formula (1) Z is not 
xe2x80x83when X is xe2x80x94Sxe2x80x94, R1 is xe2x80x94(CH2)2-5xe2x80x94, R is H, and m=1;
with the proviso that in formula (7) R4 is not hydrogen when Y is 6-F, X is xe2x80x94Oxe2x80x94, Z is 
xe2x80x83and is 2, 3 or 4;
with the proviso that in formula (18) R12 is not H when Z is 
xe2x80x83X is xe2x80x94NHxe2x80x94 or xe2x80x94N(R2)xe2x80x94 where R2 is lower alkyl, aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group and p is 1 or 2;
with the proviso that in formula (18), R12 is not H when X is xe2x80x94N(R2)xe2x80x94, where R2 is phenyl, Z is 
xe2x80x83and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;
with the proviso that in formula (19), R18 and R19 are not lower alkyl when Z is 
xe2x80x83X is xe2x80x94N(R2)xe2x80x94 and R2 is aryl and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;
with the proviso that in formula (19), when X is xe2x80x94Oxe2x80x94, Z is 
xe2x80x83and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group, R18 and R19 are not lower alkyl;
with the proviso that in formula (19), R18 and R19 are not hydrogen when R1 is xe2x80x94(CH2)2-5xe2x80x94, Z is 
xe2x80x83X is xe2x80x94Oxe2x80x94, and Y is 6-F;
all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
This invention also provides compounds selected from formula I which are suitable for acylation with (C4-C18)carboxylic acids or reactive functional derivatives thereof to form highly lipophilic esters, amides and carbamates, which compounds are also compounds of this invention. Such selected compounds possess a hydroxyl group attached to either an aliphatic or aromatic carbon atom capable of forming the highly lipophilic esters of the invention, a primary or secondary nitrogen atom including the nitrogen at the 1-position of an indazole ring system capable of forming the highly lipophilic amides of the invention. The primary or secondary nitrogen atom may alternatively be acylated with a (C4-C18)alkoxycarbonyl chloride to form a highly lipophilic carbamate derivative of the invention.
The invention also provides for the highly lipophilic compounds which provide long acting pharmaceutical effects when administered in the form of depot preparations.
This invention also provides a pharmaceutical composition, which comprises a compound of the invention and a pharmaceutically acceptable carrier therefor. In one embodiment of the invention, the pharmaceutical composition is an antipsychotic composition comprising a compound of the invention in an amount sufficient to produce an antipsychotic effect.
In addition, this invention provides a method of treating psychoses, which comprises administering to a patient a pharmaceutically effective amount of a compound of the invention.
Further, this invention provides a method of sustained release of a pharmaceutically effective amount of a lipophilic compound of the invention in the form of a depot preparation.
Finally, this invention provides a method of alleviating pain by administering to a patient a pain-relieving amount of a compound of the invention.
The compounds of this invention are useful as antipsychotic drugs and as analgesic agents. The compounds of the invention can contain a variety of different substituents and chemical groups. As used herein, when the term xe2x80x9clowerxe2x80x9d is mentioned in connection with the description of a particular group, the term means that the group it is describing contains from 1 to 6 carbon atoms.
The term xe2x80x9calkylxe2x80x9d as used herein refers to a straight or branched chain hydrocarbon group having up to 18 carbon atoms and containing no unsaturation, for example, methyl, ethyl, isopropyl, 2-butyl, neopentyl, n-hexyl or pentadecyl.
The term xe2x80x9calkoxyxe2x80x9d as used herein refers to a monovalent substituent comprising an alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy, butoxy, or pentoxy.
The term xe2x80x9calkylenexe2x80x9d as used herein refers to a bivalent radical of a lower branched or unbranched alkyl group having valence bonds on two terminal carbons thereof, for example, ethylene (xe2x80x94CH2CH2xe2x80x94), propylene (xe2x80x94CH2CH2CH2xe2x80x94), or isopropylene (xe2x80x94CH(CH3)CH2xe2x80x94).
The term xe2x80x9ccycloalkylxe2x80x9d refers to a saturated hydrocarbon group possessing at least one carbocyclic ring, the ring containing from 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl and the like.
The term xe2x80x9calkanoylxe2x80x9d refers to the radical formed by removal of the hydroxyl function from an alkanoic acid. More particularly, the term xe2x80x9calkanoylxe2x80x9d as used herein refers to an alkyl carbonyl moiety containing from 2 to 18 carbon atoms, e.g.
CH3xe2x80x94C(xe2x95x90O)xe2x80x94,
CH3xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, etc.
Examples of alkanoyl groups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl, and the like.
The term xe2x80x9calkanoic acidxe2x80x9d refers to a compound formed by combination of a carboxyl group with a hydrogen atom or alkyl group. Examples of alkanoic acids are formic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid, hexanoic acid, octanoic acid, decanoic acid, and the like.
The term xe2x80x9caryl lower alkylxe2x80x9d refers to compounds wherein xe2x80x9carylxe2x80x9d and xe2x80x9cloweralkylxe2x80x9d are as defined above.
The term xe2x80x9clower alkylthioxe2x80x9d refers to a monovalent substituent having the formula lower alkyl-Sxe2x80x94.
The term xe2x80x9cphenylsulfonylxe2x80x9d refers to a monovalent substituent having the formula phenyl-SO2xe2x80x94.
The term xe2x80x9cacylxe2x80x9d refers to a substituent having the formula lower alkyl-C(xe2x95x90O)xe2x80x94 or CF3xe2x80x94C(xe2x95x90O)xe2x80x94 or aryl-C(xe2x95x90O)xe2x80x94 or heteroaryl-C(xe2x95x90O)xe2x80x94.
The term xe2x80x9clower monoalkylaminoxe2x80x9d refers to a monosubstituted derivative of ammonia, wherein a hydrogen of ammonia is replaced by a lower alkyl group.
The term xe2x80x9clower dialkylaminoxe2x80x9d refers to a disubstituted derivative of ammonia, wherein two hydrogens of ammonia are replaced by lower alkyl groups.
The term xe2x80x9cacylaminoxe2x80x9d refers to a primary or secondary amine, wherein a hydrogen of the amine is replaced by an acyl group, where acyl is as previously defined.
The term xe2x80x9cdialkylaminocarbonylxe2x80x9d refers to a derivative of an acid, wherein the hydroxyl group of the acid is replaced by a lower dialkylamino group.
The term xe2x80x9caroylxe2x80x9d refers to a disubstituted carbonyl, wherein at least one substituent is an aryl group, where xe2x80x9carylxe2x80x9d is as previously defined.
Unless otherwise indicated, the term xe2x80x9chalogenxe2x80x9d as used herein refers to a member of the halogen family selected from the group consisting of fluorine, chlorine, bromine, and iodine.
Throughout the specification and appended claims, a given chemical formula or name shall encompass all geometric, optical and stereoisomers thereof where such isomers exist.
The compounds of this invention can be represented by the following formula: 
wherein
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(R2)xe2x80x94;
R2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl and phenylsulfonyl groups;
p is 1 or 2;
Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino;
Q1 is selected from the group consisting of: 
where Z is 
xe2x80x83and
Y2 is selected from the group consisting of: 
in which (R1) is xe2x80x94CR24R27xe2x80x94(CR23R24)nxe2x80x94CR24R27xe2x80x94 where n is 0,1,2, or 3; or
xe2x80x94CHR24xe2x80x94CHxe2x95x90CHxe2x80x94CHR24xe2x80x94,
xe2x80x94CHR24xe2x80x94Cxe2x95x90Cxe2x80x94CHR24xe2x80x94, 
xe2x80x94CHR24xe2x80x94CHxe2x95x90CHxe2x80x94CR23R24xe2x80x94CHR24xe2x80x94,
xe2x80x94CHR24xe2x80x94CR23R24xe2x80x94CHxe2x95x90CHxe2x80x94CHR24xe2x80x94,
xe2x80x94CHR24xe2x80x94Cxe2x89xa1Cxe2x80x94CR23R24xe2x80x94CHR24xe2x80x94, or
xe2x80x94CHR24xe2x80x94CR23R24xe2x80x94Cxe2x89xa1Cxe2x80x94CHR24xe2x80x94,
the xe2x80x94CHxe2x95x90CHxe2x80x94 bond being cis or trans;
R23 is hydrogen, (C1-C18) linear alkyl, phenyl, hydroxy, (C1-C18)alkoxy, aryloxy, aryl(C1-C18)alkyloxy, (C1-C18)alkanoyloxy, hydroxy(C1-C6)alkyl, (C1-C18)alkoxy(C1-C6)alkyl, phenyl(C1-C6)alkyloxy, aryl(C1-C18)alkyloxy(C1-C6)alkyl or (C1-C18)alkanoyloxy(C1-C6)alkyl or 
where Z1 is lower alkyl, xe2x80x94OH, lower alkoxy, xe2x80x94CF, xe2x80x94NO2, xe2x80x94NH2 or halogen; and
R24 is hydrogen, (C1-C18) linear alkyl, phenyl, hydroxy(C1-C6)alkyl,
(C1-C18)alkoxy(C1-C6)alkyl, phenyl(C1-C6)alkyloxy, aryl(C1-C18)alkyloxy(C1-C6)alkyl or (C1-C18)alkanoyloxy(C1-C6)alkyl or 
where Z1 is as previously defined;
R27 is hydrogen or R24 and R27 taken together with the carbon to which they are attached form Cxe2x95x90O or Cxe2x95x90S; and
R and m are as defined hereinafter; 
where R1 is as previously defined, and R3 is hydrogen or xe2x80x94OCH3; 
where R1 is as previously defined; and
R4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C1-C6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C1-C18)acyl amino, (C1-C18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94(C1-C18straight or branched chain) alkyl or xe2x80x94C(xe2x95x90O)-aryl;
in which aryl is phenyl or 
where R5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; 
where R1 and R4 are as previously defined; 
where either one of Xy or Xz is C(xe2x95x90O)xe2x80x94 and the other is xe2x80x94CH2xe2x80x94; and R5xe2x80x2 is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine; and R1 is as previously defined; 
where R1 and R4 are as previously defined; 
where A is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94C(xe2x95x90CH2)xe2x80x94, xe2x80x94C(xe2x95x90O)CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CR26xe2x95x90Nxe2x80x94 or xe2x80x94CR25R26xe2x80x94;
R25 is hydrogen, (C1-C6)alkyl, hydroxy or (C1-C18)alkanoyloxy;
R26 is hydrogen or (C1-C6)alkyl;
either one of By and Bz is CH or N and the other is CH;
U is O or S;
q is 1, 2, 3 or 4 and R1 and R4 areas previously defined; 
where R1 is as previously defined; 
wherein R1, R4 and q are as defined above; and
R28 is hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl or substituted phenyl; 
wherein R1, R4and q are as defined above;
R29 and R30 are hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl or substituted phenyl;
R31 and R32 are hydrogen, hydroxy, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl, substituted phenyl, hydroxymethyl, or CHOR33 where R33 is (C1-C18)alkanoyl; or
either R29 and R30 taken together or R31 and R32 taken together with the carbon group to which they are attached form a Cxe2x95x90O or Cxe2x95x90S group; 
where R1, R4, R28, R29, R30, R31, R32 and q are as defined above; 
where R1, R4, R28, R29, R30, R31, R32 and q are as defined above; 
wherein R1 and R4 are previously defined and m is defined hereinafter; 
where R1 is as previously defined;
Q2 is S, NH, or xe2x80x94CH2xe2x80x94; and
R and m are as defined hereinafter; 
where R1 is as previously defined; 
where R1 and R4 are as previously defined and m is defined hereinafter; 
where R1 and R4 are as previously defined and m is defined hereinafter;
xe2x80x94R1xe2x80x94Oxe2x80x94R12xe2x80x83xe2x80x83(18)
where R12 is selected from the group consisting of:
hydrogen,
alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C18 straight chain or branched) alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94NR13R14,
xe2x80x94C(xe2x95x90O)xe2x80x94NR15R16,
xe2x80x94S(xe2x95x90O)2xe2x80x94R17, and 
where R13 is selected from the group consisting of hydrogen and (C1-C18) alkyl groups;
where R14 is selected from the group consisting of hydrogen and (C1-C18) alkyl groups;
where NR15R16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;
where R17 is selected from the group consisting of (C1-C18)alkyl and aryl groups;
where R4 is previously defined and m is defined hereinafter;
xe2x80x94R1xe2x80x94NR18R19xe2x80x83xe2x80x83(19)
where R18 and R19 are independently selected from the group consisting of:
hydrogen,
(C1-C18 straight or branched chain) alkyl;
xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94(C1-C18) alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C18) alkyl;
xe2x80x94C(xe2x80x94O)-pyridyl; 
where NR18R19 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;
where the piperidinyl or piperazinyl ring is optionally substituted by 
where X, Y, p, R1, R4 and R28 are as previously defined and m is defined hereinafter;
xe2x80x94R1xe2x80x94Sxe2x80x94R12xe2x80x83xe2x80x83(20)
where R1 and R12 are as previously defined; 
where R1, R4 and R28 are as previously defined; and
where
R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl,
xe2x80x94C(xe2x95x90O)-alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94O-alkyl,
xe2x80x94C(xe2x95x90O)-aryl,
xe2x80x94C(xe2x95x90O)-heteroaryl,
xe2x80x94CH(OR7)-alkyl,
xe2x80x94C(xe2x95x90W)-alkyl,
xe2x80x94C(xe2x95x90W)-aryl, and
xe2x80x94C(xe2x95x90W)-heteroaryl;
alkyl is (C1-C18)alkyl;
aryl is as previously defined;
heteroaryl is 
Q3 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94;
W is CH2 or CHR8 or Nxe2x80x94R9;
R7 is hydrogen, alkyl, or alkanoyl;
R8 is lower alkyl;
R9 is hydroxy, alkoxy, or xe2x80x94NHR10; and
R10 is hydrogen, lower alkyl, (C1-C18)acyl, aryl, xe2x80x94C(xe2x95x90O)-aryl or xe2x80x94C(xe2x95x90O)-heteroaryl,
where aryl and heteroaryl are as defined above; and
m is 1, 2, or 3;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94Sxe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, Y is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy or trifluoromethyl, and p is 1 or 2;
with the proviso that in formula (4) R4 is not H when R1 is xe2x80x94(CH2)2-5xe2x80x94, Z is not 
xe2x80x83X is xe2x80x94Sxe2x80x94, Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl, and p is 1 or 2;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94NHxe2x80x94 or xe2x80x94N(R2)xe2x80x94, Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl and Q2 is xe2x80x94CH2xe2x80x94;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94Oxe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, Y is hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen, and p is 1 or 2;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94Sxe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2, R is hydrogen, and m is 1;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94N(R2)xe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, R is chlorine, fluorine, bromine, iodine, lower alkyl, lower alkoxy, lower alkyl thio, lower mono- or dialkylamino, amino, cyano, hydroxy, trifluoromethyl; R2 is aryl; Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94NHxe2x80x94 or xe2x80x94N(R2)xe2x80x94, where R2 is lower alkyl, aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2 and Q2 is xe2x80x94CH2xe2x80x94;
with the proviso that Y2 is not the moiety of formula (8) when Z is 
xe2x80x83X is O, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;
with the proviso that in formula (1) Z is not 
xe2x80x83when X is O or S, Y is hydrogen, R is hydrogen, (C1-C4)alkyl, chlorine, fluorine, bromine, iodine, cyano, (C1-C4)alkoxy, aryl, xe2x80x94COOR25 where R25 is (C1-C4)alkyl;
with the proviso that in formula (1) Z is not 
xe2x80x83when X is xe2x80x94Sxe2x80x94, R1 is xe2x80x94(CH2)2-5xe2x80x94, R is H, and m=1;
with the proviso that in formula (7) R4 is not hydrogen when Y is 6-F, X is xe2x80x94Oxe2x80x94, Z is 
xe2x80x83and n is 2, 3 or 4;
with that the proviso that in formula (18) R12 is not H when Z is 
xe2x80x83X is xe2x80x94NHxe2x80x94 or xe2x80x94N(R2)xe2x80x94 where R2 is lower alkyl, aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group and p is 1 or 2;
with the proviso that in formula (18), R12 is not H when X is xe2x80x94N(R2)xe2x80x94, where R2 is phenyl, Z is 
xe2x80x83and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;
with the proviso that in formula (19), R18 and R19 are not lower alkyl when Z is 
xe2x80x83X is xe2x80x94N(R2)xe2x80x94 and R2 is aryl and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;
with the proviso that in formula (19), when X is xe2x80x94Oxe2x80x94, Z is 
xe2x80x83and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group, R18 and R19 are not lower alkyl;
with the proviso that in formula (19), R18 and R19 are not hydrogen when R1 is xe2x80x94(CH2)2-5xe2x80x94, Z is 
xe2x80x83X is xe2x80x94Oxe2x80x94, and Y is 6-F;
all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
When the compounds of the invention are represented by the following formula: 
where Q1 is selected from the group consisting of: 
the substituent X in formula (I) is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(R2)xe2x80x94. When the substituent X is xe2x80x94Oxe2x80x94, the compounds of the invention contain a 1,2-benzisoxazole nucleus, and when X is xe2x80x94Sxe2x80x94, the compounds of the invention contain a 1,2-benzisothiazole nucleus. When X is xe2x80x94NHxe2x80x94 or xe2x80x94N(R2)xe2x80x94, the compounds of the invention contain the indazole nucleus.
When p in formula (I) is 1, the substituent Y is selected from the group consisting of hydrogen, lower alkyl, hydroxyl, halogen, lower alkoxy, xe2x80x94CF3, xe2x80x94NO2, and xe2x80x94NH2. The substituent Y is preferably in the 5- or 6-position of the ring. Moreover, in the preferred embodiments of the invention, the substituent Y is hydrogen, hydroxy, chlorine, bromine, or fluorine, and in the particularly preferred compounds of the invention, Y is fluorine, especially in the 6-position of the ring.
When p in formula (I) is 2 and X is xe2x80x94Oxe2x80x94, each Y substituent can be independently selected from lower alkoxy, hydroxy or halogen groups, preferably methoxy groups.
When the substituent Y2 has the formula (b)(1): 
and R1 contains unsaturation, R1 preferably has the formula
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94.
When the substituent Y2 has the formula (b)(3): 
the substituent R4 is preferably hydrogen or (C1-C6)alkyl carbonyl and n is 3.
When the substituent Y2 has the formula (b)(4): 
the substituent R4 is preferably hydrogen or xe2x80x94C(xe2x95x90O)CH3 and n is preferably 1 or 2.
When the substituent Y2 has the formula (b)(5): 
the substituent R5xe2x80x2 is preferably xe2x80x94OCH3 and n is preferably 3.
When the substituent R4 has the formula (b)(6): 
the substituent R4 is preferably xe2x80x94C(xe2x95x90O)CH3 and n is preferably 3.
When the substituent Y2 has the formula (b)(7): 
the substituent R4 is preferably hydrogen or methyl and n is preferably 2.
When the substituent Y2 has the formula (b)(8): 
the value of n is preferably 3 or 4.
When the substituent Y2 has the formula (b)(9): 
the substituent R6 is preferably xe2x80x94CH2xe2x80x94CHxe2x95x90CH2xe2x80x94CH2xe2x80x94 when R6 contains unsaturation.
When the substituent R is 
the substituent Q3 is preferably xe2x80x94CHxe2x95x90N; and
the substituent W is preferably CH2, the substituent R8 in CHR8 is preferably CH3, the substituent R9 in Nxe2x80x94R9 is preferably hydroxy, lower alkoxy, or NH2, and the substituent R10 in NHR10 is preferably hydrogen.
The value of n in the foregoing formulas can be 2, 3, 4, or 5, and preferably is 2, 3, or 4. In the particularly preferred compounds of the invention n is 2 or 3.
When X in the compounds of the invention is xe2x80x94N(R2)xe2x80x94, the substituent R2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkanoyloxy and phenylsulfonyl groups.
The substituent Z can be 
in which case the compounds of the invention are heteroarylpiperidine derivatives, or 
in which case the compounds are heteroarylpiperazine derivatives. When the substituent Q1 has the formula 
the compounds of the invention are heteroarylpyrrolidines. The preferred compounds of the invention are the heteroarylpiperidines, i.e. compounds in which Z is 
The compounds of the invention can contain one, two, or three R-substituents. The substituent R can be hydrogen, lower alkyl, (C1-C18)alkoxy, hydroxyl, carboxyl, Cl, F, Br, I, amino, (C1-C18)mono or dialkyl amino, xe2x80x94NO2, lower alkyl thio, xe2x80x94OCF3 cyano, acylamino, xe2x80x94CF3, trifluoroacetyl (i.e. xe2x80x94C(xe2x95x90O)xe2x80x94CF3), aminocarbonyl (i.e. xe2x80x94C(xe2x95x90O)xe2x80x94NH2), dialkylaminocarbonyl,
formyl,
xe2x80x94C(xe2x95x90O)-alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94O-alkyl,
xe2x80x94C(xe2x95x90O)-aryl,
xe2x80x94C(xe2x95x90O)-heteroaryl, or
xe2x80x94CH(OR7)-alkyl,
xe2x80x94C(xe2x95x90W)-alkyl,
xe2x80x94C(xe2x95x90W)-aryl, or
xe2x80x94C(xe2x95x90W)-heteroaryl;
alkyl is (C1-C18) alkyl;
aryl is phenyl or 
where R5 is hydrogen, lower alkyl, (C1-C6)alkoxy, hydroxy, Cl, F, Br, I, (C1-C18)alkylamino, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3;
heteroaryl is 
Q3 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94,
W is CH2 or CHR8 or Nxe2x80x94R9;
R7 is hydrogen, alkyl, or alkanoyl;
R8 is lower alkyl;
R9 is hydroxy, alkoxy, or xe2x80x94NHR10; and
where R10 is hydrogen, lower alkyl, (C1-C18)acyl, aryl, xe2x80x94C(xe2x95x90O)-aryl or xe2x80x94C(xe2x95x90O)- heteroaryl, where aryl and heteroaryl are as defined above; and
m is 1, 2, or 3.
When the compounds of the invention contain two or three R-substituents, each of the R-substituents can be independently selected from the above substituents. Preferably, each of the R-substituents is selected from the group consisting of hydrogen, (C1-C18) alkyl, (C1-C18)alkoxy, hydroxyl, xe2x80x94COCF3, (C1-C18)alkanoyl, Cl, F, Br, I, (C1-C3)alkylamino, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94OCF3,
xe2x80x94C(xe2x95x90O)-lower alkyl,
and
xe2x80x94CH(OR7)-lower alkyl.
The compounds of the present invention are prepared in the following manner. The substituents R, R1, R2, R3, etc., X, Y, and Z and the integers m, n, and p are as defined above unless indicated otherwise.
The compounds of the invention can generally be prepared by reacting a piperidine or a piperazine of the formula: 
or a pyrrolidine of the formula: 
under alkylating conditions with a compound of the formula:
HALxe2x80x94Y2;xe2x80x83xe2x80x83(4)
where HAL is Cl, Br, or I. The procedures that can be employed for preparing the piperidines, the piperazines, and the pyrrolidines and the alkylating agents identified by the above formulas will now be described in detail.
Compounds of the formulae: 
for use in synthesizing the indazoyl-substituted piperazines of the invention can be prepared as follows.
A substituted aryl ester of formula (7) is selected, 
where R11 is lower alkyl and Hal is a halogen selected from the group consisting of Cl, Br, and I. The ester of formula (7) is reacted with hydrazine, H2NNH2, under standard hydrazide formation conditions. Typically, the reaction is carried out in a nonreactive solvent, e.g. ethanol, methanol, or toluene, at a temperature of ambient temperature to the reflux temperature of the solvent for 4 to 16 hours to form a hydrazide of formula (8): 
The hydrazide of formula (8) is reacted with a phenyl sulfonyl halide of the formula 
where Hal is a halogen selected from the group consisting of Cl and Br, to form a compound of the formula 
Typically this reaction is carried out in a basic solvent, such as pyridine or collidine, at a temperature of 0xc2x0 to 30xc2x0 C. for 2 to 16 hours.
The compound of formula (10) in turn is reacted neat with thionyl chloride at a temperature of 50xc2x0 to 79xc2x0 C. (reflux temperature) for 2 to 16 hours to form a compound of formula (11) 
Compound (11) is reacted with a compound of formula (12), 
where R11 is lower alkyl, under conventional nucleophilic reaction conditions, for example in an inert solvent, such as tetrahydrofuran (THF), toluene, or diethylether, at a temperature of 50xc2x0 to 50xc2x0 C. for 1 to 16 hours to form a compound having the formula 
The compound of formula (13) is then reacted with a condensation agent, such as copper, copper-bronze, or cuprous oxide, in a solvent such as dimethylformamide, dimethylacetamide, or tetramethylurea, at a temperature of 120xc2x0 to 177xc2x0 C. for 1 to 16 hours to form a piperazine-substituted phenylsulfonyl indazole of the formula 
A cyano-substituted piperazine phenylsulfonyl indazole is then formed by reacting the compound of formula (14) with a conventional cyanation source, such as a halo-cyanide, e.g. BrCN or ClCN, under conventional cyanation conditions, typically in an inert solvent, e.g. dimethylsulfoxide (DMSO) or CHCl3, at ambient temperature for 2 to 16 hours to form a compound of formula 
The compound of formula (15) is then subjected to reduction by means of a metal hydride, e.g. lithium aluminum hydride (LiAlH4). Typically the reduction is carried out under standard reduction conditions in a solvent, such as tetrahydrofuran or diethyl ether, at a temperature of 35xc2x0 to 67xc2x0 C. for 6 to 16 hours to form a compound of formula (16): 
A compound of formula (16) can be formed in an alternative manner by first reacting a compound of formula (14) with a strong base, such as a metal alcoholate, e.g. sodium methoxide, sodium ethoxide, or sodium butoxide, or with KOH in tetrahydrofuran to form a compound of formula (17): 
This reaction is typically carried out in a polar solvent, such as for example CH3OH or C2H5OH, at a temperature of ambient to 50xc2x0 C. for 1 to 16 hours.
Alternatively, the compound of formula (17) can be formed by reducing compound (14) with LiAlH4 under conditions as previously described.
The compound of formula (17) in turn can be reacted with a cyanation reagent, as previously described, to form a cyano substituted piperazine indazole of the formula 
which in turn can be reduced with a metal hydride, as previously described, to form a compound of formula (16).
In an alternative embodiment, a compound of formula (18) can be reacted with an aqueous mineral acid, e.g. H2SO4 or HCl, at a temperature of 50xc2x0 to 120xc2x0 C. for 2 to 16 hours to form a compound of formula (16).
A compound of the formula: 
can be prepared according to conventional techniques. Suitable procedures are described in J. Med. Chem. 1986, 22:359. Compounds of formula (19) are useful for synthesizing the benzisoxazole substituted piperazines of the invention.
A compound of the formula: 
for use in synthesizing the benzisothiazole substituted piperazines of the invention can be prepared according to the techniques described in J. Med. Chem. 1986, 22:359, United Kingdom Patent (GB) 2 163 432 A and Tetrahedron Letters, Vol 34, No.41, pp6525-6528, 1993.
A compound of the formula: 
for use in synthesizing the indazole-substituted piperidines of the invention can be prepared using known techniques. For example, suitable techniques are described in substantial detail in U.S. Pat. No. 4,710,573.
A compound of the formula: 
can be prepared by following the teachings from several sources. For example, U.S. Pat. No. 4,355,037 contains a detailed description of compounds of formula (23) and of methods for preparing the compounds. Additional disclosure of methods for preparing the compounds of formula (23) can be found in U.S. Pat. No. 4,327,103 and in Strupczewski et al., J. Med. Chem., 28:761-769 (1985). The compounds of formula (23) can be employed in the synthesis of the benzisoxazole substituted piperidines of the invention.
Certain 3-(4-piperidinyl)-1,2-benzisothiazoles can be employed in the synthesis of the N-(aryloxyalkyl)heteroaryl piperidines of the invention. Specifically, a benzisothiazole of the formula: 
can be reacted with the alkylating agent previously described to form the N-(aryloxyalkyl)heteroarylpiperidines of the invention. Compounds of formula (24) and their methods of preparation are described in detail in U.S. Pat. No. 4,458,076.
The compounds described in Sections 1-6 above can be reacted with alkylating agents as is known in the art. For example, when Y2 is as described in formula (1), an alkylating agent of the formula: 
is reacted to form the N-(aryloxyalkyl)heteroarylpiperidines, piperazines, and pyrrolidines of the invention. The alkylating agents of formula (4) and methods for preparing the alkylating agents are described in U.S. Pat. No. 4,366,162. Additional disclosure can be found in South African publication EA 86 14522. In addition, procedures for making alkylating agents are described in the following Examples. These procedures can be employed to make other alkylating agents for use in this invention.
The heteroarylpiperidines, piperazines, and pyrrolidines described in Sections 1-6 above can be reacted under alkylating conditions with the alkylating agents described in Section 7 to form selected compounds of this invention. The reaction can be carried out by dissolving the reagents in an inert solvent, such as dimethylformamide, acetonitrile, or butanol, and allowing the reagents to react from a temperature of 50xc2x0 C. to refluxing of the solvent in the presence of an acid receptor, such as a base. Examples of suitable bases are alkali metal carbonates, such as potassium carbonate, sodium carbonate, or sodium bicarbonate. The reaction can be carried out with or without a catalytic amount of an alkaline iodide, such as potassium iodide or sodium iodide, for a time sufficient to form a compound of formula (I) of the invention. Generally, the alkylation reaction is carried out for about 4 to about 16 hours, depending on reactivity of the reagents. The reaction temperature can vary from about 50xc2x0 to about 120xc2x0 C. The products can be isolated by treating the reaction product with water, extracting the product into an organic solvent that is immiscible in water, washing, drying, and concentrating the organic solvent to yield the free base, and then, if indicated, converting the resulting compound to an acid addition salt in a conventional manner.
In addition, the compounds of formula 19 where R18R19 are both hydrogen may be prepared from the phthalimido compound of formula 7 by treatment with base such as, for example, hydrazine as is known in the art.
More specifically, certain of the compounds of the invention can be synthesized by the following methods:
A. Synthesis of Phthalimides
The phthalimido compounds of the invention of formula (25) can be synthesized 
in several ways.
1. Alkylation with an N-Haloalkylphthalimide
The heterolarylpiperidines, piperazines and pyrrolidines described in Sections 1-6 above are alkylated under known conditions using the appropriate haloalkylphthalimide, preferably an N-bromoalkylphthalimide (26), in a nonprotic 
organic solvent such as acetonitrile in the presence of a base such as potassium carbonate at a temperature of from about room temperature to about 120xc2x0 C., preferably from about 80xc2x0 C. to about 100xc2x0 C.
2. Reaction with a Phthalic Anhydride
The heteroarylpiperidines, piperazines and pyrrolidines described in Sections 1-6 above are first reacted with a haloalkylnitrile to form the corresponding substituted nitrile (27) wherein R is a substituent as defined for R1 above. The reaction is carried out in a polar, nonprotic organic solvent such as 
acetonitrile in the presence of a base such as potassium carbonate at a temperature of from about room temperature to about 120xc2x0 C., preferably from about 80xc2x0 C. to about 100xc2x0 C.
The nitrile is then reduced, for example with lithium aluminum hydride in an organic solvent such as tetrahydrofuran at a temperature of from about 0xc2x0 C. to about 80xc2x0 C. preferably at about room temperature to yield the corresponding primary amine (28). 
The amine(28) is reacted with phthalic anhydride or a substituted phthalic anhydride or the corresponding phthalic acid under known conditions, for example in dichloromethane or dimethylformamide at temperatures of from about 10xc2x0 C. to about 150xc2x0 C. to yield the corresponding phthalimido compound. Preferred conditions for the reaction include dichloromethane at room temperature or dimethylformamide at 135xc2x0 C.
B. Synthesis of Isoindolines
The isoindolines of Formula (29) can be prepared by the following routes. 
1. Condensation with an xcex1,xcex1xe2x80x2-Dibromo-ortho-xylene
The amine (28) is reacted with an xcex1,xcex1xe2x80x2-dibromo-ortho-xylene to obtain the isoindoline. The reaction is carried out in an organic solvent such as acetonitrile in the presence of a base such as potassium carbonate at temperatures of from about room temperature to about 150xc2x0 C., preferably from about 75xc2x0 C. to about 100xc2x0 C.
2. Reduction of a Phthalimide
Alternatively, a phthalimido compound of the invention is reduced, for example with lithium aluminum hydride in an organic solvent such as tetrahydrofuran at a temperature of from about 0xc2x0 C. to about 100xc2x0 C., preferably from about 70xc2x0 C. to about 90xc2x0 C.
C. Synthesis of Tetrahydroquinolines and Tetrahydroisoquinolines
The tetrahydroquinolines and tetrahydroisoquinolines of the invention can be prepared by alkylating the heteroarylpiperidine, piperazine and pyrrolidines (3, 3A) with the appropriate 2-bromoacetyltetrahydroquinoline or 2-bromoacetyltetrahydroisoquinoline in the presence of a polar organic solvent such as acetonitrile in the presence of a base such as potassium carbonate at temperatures of from about room temperature to about 150xc2x0 C., preferably from about 75xc2x0 C. to about 100xc2x0 C. to form the corresponding amide (30, 30a). 
The amide (30, 30a) is reduced, for example with lithium aluminum hydride in an organic solvent such as tetrahydrofuran at a temperature of from about 0xc2x0 C. to about 80xc2x0 C. preferably at about room temperature to yield the alkyl compound.
Selected compounds of the invention possess a hydroxyl group attached to either an aliphatic or aromatic carbon capable of forming the highly lipophilic esters of this invention or possess a primary or secondary nitrogen atom including the nitrogen at the 1-position of an indazole ring system capable of forming the highly lipophilic amides of this invention. The primary or secondary nitrogen atom may alternatively be acylated with a C4-C18 alkoxycarbonyl chloride to form a highly lipophilic carbamate derivative. Representatives of such alcohols and amines and their highly lipophilic derivatives are found in the Examples of this invention.
It is known in the art that long acting derivatives of drugs may be obtained by such transformation. European Patent Publication No. 260,070 discloses the prolonged action of haloperidol decanoate ester. International Publication No. WO 92/06089 discloses sustained release amide derivatives of sertindole.
Following are typical examples of compounds of the invention that can be prepared by following the techniques described above:
1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone;
1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;
1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;
1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]-ethanone;
1-[4-[2-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone fumarate;
1-[4-[4-[4-(1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone fumarate;
1-[4-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone;
4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-xcex1-methylbenzenemethanol;
1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone;
1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone;
1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone;
1-[4-[3-[4-(1H-indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;
1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;
1-[4-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone fumarate;
1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;
6-fluoro-3-[1-[3-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazole fumarate;
[4-[3-[4-(fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]phenylmethanone;
1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;
1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone;
1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone fumarate;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methylphenyl]ethanone;
1-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-5-methylphenyl]ethanone;
N-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]acetamide hemifumarate;
6-chloro-3-(1-piperazinyl)-1H-indazole;
1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methylphenyl]ethanone hemifumarate;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;
1-[4-[3-[4-(6chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone;
1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone;
4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzonitronile;
1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;
1-[4-[3-[4-(1-benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3methoxyphenyl]ethanone sesquifumarate;
1-[4-[4-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone;
1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone hemifumarate;
1-[3,5-dibromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;
1-[4-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]ethanone;
6-fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole;
1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]ethanone;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methylmercaptophenyl]ethanone;
1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]phenylmethanone;
1-[3-bromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;
3-[1-[3-[4-(1-ethoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole hydrochloride;
3-[1-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole fumarate;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy-3-methoxyphenyl]pentanone;
2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-N-methylbenzenamine hemifumarate;
3-[1-[3-(4-bromo-2-methoxyphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-propanone;
4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylamino)phenyl]ethanone;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-ethoxyphenyl]ethanone;
N-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-dimethylaminophenyl]ethanone;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methoxyphenyl]ethanone hydrochloride;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2,2,2-trifluoroethanone;
4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-xcex1-methylbenzenemethanol;
2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]aniline dihydrochloride;
N-[5-acetyl-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide;
3-[1-[3-(4-ethyl-3-methoxyphenoxy)propyl]-4-piperidinyl]6-fluoro-1,2-benzisoxazole hydrochloride;
1-[3,5-dimethoxy-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;
N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide hemifumarate;
3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]aniline;
3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyaniline;
1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy-3-methylaminophenyl]ethanone fumarate;
N-[3-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]acetamide;
1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrochloride;
N,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxime;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]-ethanone oxime O-methyl ether;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrazone;
6-fluoro-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy]propyl]-4-piperidinyl]-1,2-benzisoxazole hydrochloride;
(Z)-1-[4-[4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone;
(Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3methoxyphenyl]ethanone;
(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-hydroxyphenyl]ethanone hydrochloride;
(E)-1-[3[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanone;
6-(3-chloropropoxy)-5-methoxyindole;
6-fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole;
6-fluoro-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole hemifumarate;
6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole;
6-fluoro-3-[1-(2-pyrimidinoxy)propyl]-4-piperidinyl]-1,2-benzisoxazole fumarate;
6-aceto-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan;
2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan;
2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-1,4-benzodioxan;
6-(3-chloropropoxy)-7-methoxy-1-tetralone;
6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-tetralone;
N-(3-chloropropyl)-2-benzoxazolinone;
N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone;
N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone;
N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimide;
1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine dihydrochloride;
cis-2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)propyl)hexahydro-1H-isoindole-1,3-dione hydrochloride;
N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butyl]phthalimide;
1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine dihydrochloride;
cis-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl) butyl)hexahydro-1H-isoindole-1,3-dione hydrochloride;
1-[4-[[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]ethanone;
4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2xe2x80x2-methoxyphenyl) butylpiperidine maleate;
4-(4-bromobutyl)-1-(1,3dithian-2-yl)ethylbenzene;
1-[4-(1,3-dithian-2-yl)ethyl]phenyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)butylpiperidine;
1-[4-(4xe2x80x2-acetophenyl)butyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-methoxyphenyl]ethanone;
(2,4-difluorophenyl)-[1-(phenylmethyl)-3-pyrrolidinyl] methanone oxalate;
6-fluoro-3-[1-phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazole fumarate;
(E)-1-[4-[(4-bromo-2-butenyl)oxy]-3-methoxyphenyl]ethanone;
4-(3-chloropropoxy)-3-methoxybenzaldehyde;
6-fluoro-3-(3-pyrrolidinyl)-1,2-benzisoxazole hydrochloride;
1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] propylamino]-3-hydroxyphenyl]ethanone;
1-[3-acetylamino-4-(3-chloropropoxy)phenyl]ethanone;
N-[2-(3-hydroxypropoxy)phenyl]acetamide;
4-(3-chloropropoxy)-3-methoxybenzaldehyde;
(xc2x1)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;
(S)-(+)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;
(R)-(xe2x88x92)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;
1-[4-[3-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2,2-dimethylpropoxy]-3-methoxyphenyl]ethanone;
(xc2x1)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-phenylpropoxy]-3-methoxyphenyl]ethanone;
(xc2x1)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-(3-chlorophenyl)propoxy]-3-methoxyphenyl]ethanone;
(xc2x1)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-(phenylmethyl)propoxy]-3-methoxyphenyl]ethanone;
(xc2x1)-1-[4-[3-[4-(fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-methylpropoxy]-3-methoxyphenyl]ethanone;
(xc2x1)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methylpropoxy]-3-methoxyphenyl]ethanone;
(xc2x1)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl ]-3-methylbutoxy]-3-methoxyphenyl]ethanone;
(xc2x1)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-phenylbutoxy]-3-methoxyphenyl]ethanone;
(xc2x1)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-(2-phenylethyl)butoxy]-3-methoxyphenyl]ethanone;
(xc2x1)-[4-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-methylethoxy]-3-methoxyphenyl]ethanone;
(E)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-methyl-2-butenyl]oxy]-3-methoxyphenyl]ethanone;
(Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methyl-2-butenyl]-oxy]-3-methoxyphenyl]ethanone;
(xc2x1)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-propyl-2-butenyl]oxy]-3-methoxyphenyl]ethanone;
(S)-(+)-1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-2-methylpropoxy]- methoxyphenyl]ethanone;
(R)-(xe2x88x92)-1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;
(xc2x1)-1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-3-methylbutoxy]-3-methoxyphenyl]ethanone;
(xc2x1)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-phenylpropoxy]-3-methoxyphenyl]ethanone; and
(xc2x1)-6-fluoro-3-[1-[3-(2-methyl-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazole.
The compounds of the present invention are useful for treating psychoses by virtue of their ability to elicit an antipsychotic response in mammals. Antipsychotic activity is determined in the climbing mice assay by a method similar to those described by P. Protais, et al., Psychopharmacol., 50:1 (1976) and B. Costall, Eur. J. Pharmacol., 50:39 (1978).
Subject CK-1 male mice (23-27 grams) are group-housed under standard laboratory conditions. The mice are individually placed in wire mesh stick cages (4xe2x80x3xc3x9710xe2x80x3) and are allowed one hour for adaption and exploration of the new environment. Then apomorphine is injected subcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for 30 minutes. Compounds to be tested for antipsychotic activity are injected intraperitoneally or given oral doses at various time intervals, e.g. 30 minutes, 60 minutes, etc. prior to the apomorphine challenge at a screening dose of 10-60 mg/kg.
For evaluation of climbing, 3 readings are taken at 10, 20, and 30 minutes after apomorphine administration according to the following scale:
Mice consistently climbing before the injection of apomorphine are discarded.
With full-developed apomorphine climbing, the animals are hanging on to the cage walls, rather motionless, over long periods of time. By contrast, climbs due to mere motor stimulation usually only last a few seconds.
The climbing scores are individually totaled (maximal score: 6 per mouse over 3 readings) and the total score of the control group (vehicle intraperitoneally-apomorphine subcutaneously) is set to 100%. ED50 values with 95% confidence limits, calculated by a linear regression analysis, of some of the compounds of the present invention as well as a standard antipsychotic agent are presented in Table 1.
Antipsychotic response is achieved when the compounds of the present invention are administered to a subject such treatment as an effective oral, parenteral, or intravenous does of from 0.01 to 50 mg/kg of body weight per day. It is be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and they do not, to any extent, limit the scope or practice of the invention.
Some of the compounds of the present invention are also useful as analgetics due to their ability to alleviate pain in mammals. The analgetic utility is demonstrated in the phenyl p-quinone writhing assay in mice, a standard assay for analgesia: Proc. Soc. Exptl. Biol. Med., 95:729 (1957). Thus, for instance, the subcutaneous dose effecting an approximately 50% inhibition of writhing (ED50) in mice produced in this assay is as shown Table 2.
Analgesia is achieved when the compounds of the present invention are administered to a subject requiring such treatment as an effective oral, parenteral, or intravenous dose of from 0.01 to 100 mg/kg of body weight per day. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention.
Effective amounts of the compounds of the present invention can be administered to a subject by any one of several methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions.
The compounds of the present invention, while effective themselves, can be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility, and the like. Preferred pharmaceutically acceptable addition salts include salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid, and the like; salts of monobasic carboxylic acids, for example, acetic acid, propionic acid, and the like; salts of dibasic carboxylic acids, for example, maleic acid, fumaric acid, and the like; and salts of tribasic carboxylic acids, such as carboxysuccinic acid, citric acid, and the like.
Effective quantities of the compounds of the invention can be administered orally, for example, with an inert diluent or with an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purposes of oral therapeutic administration, compounds of the invention can be incorporated with an excipient and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, and the like. These preparations should contain at least 0.5% of active compound of the invention, but can be varied depending upon the particular form and can conveniently be between 4% to about 70% of the weight of the unit. The amount of active compound in such a composition is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0-300 milligrams of the active compound of the invention.
Tablets, pills, capsules, troches, and the like can also contain the following ingredients: a binder, such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient, such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, corn starch, and the like; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose; or saccharin, or a flavoring agent, such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms can contain various materials that modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills can be coated with sugar, shellac, or other enteric coating agents. A syrup can contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colorings, and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purpose of parenteral therapeutic administration, the active compound of the invention can be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but can be varied between 0.5 and about 50% of the weight thereof. The amount of active compounds in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound.
Solutions or suspensions can also include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampules, disposable syringes, or multiple dose vials made of glass or plastic.
The highly lipophilic esters, amides and carbamates of the present invention are capable of sustained release in mammals for a period of several days or from about one to four weeks when formulated and administered as depot preparations, as for example, when injected in a properly selected pharmaceutically acceptable oil. The preferred oils are of vegetable origin such as sesame oil, cottonseed oil, corn oil, coconut oil, soybean oil, olive oil and the like, or they are synthetic esters of fatty acids and polyfunctional alcohols such as glycerol or propyleneglycol.
The depot compositions of the present invention are prepared by dissolving a highly lipophilic ester, amide or carbamate of the instant invention in a pharmaceutically acceptable oil under sterile conditions. The oil is selected so as to obtain a release of the active ingredient over a desired period of time. The appropriate oil may easily be determined by consulting the prior art, or without undue experimentation by one skilled in the art.
An appropriate dose of a compound in accordance with this embodiment of the invention is from about 0.01 to 10 mg/kg of body weight per injection. Preferably, the depot formulations of this invention are administered as unit dose preparations comprising about 0.5 to 5.0 ml of a 0.1 to 20% weight/weight solution of compound in the oil. It is to be understood that the doses set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention.